Bottom Line:
Net population benefit was estimated in aggregated QALYs.In the base-case scenario, treatment effects were uniformly positive, and net benefits increased with increasing age at screening.Highly efficacious presymptomatic screen and treat strategies for AD are likely to produce substantial aggregate population benefits that are likely greater than the benefits of aspirin in primary prevention of moderate risk cardiovascular disease (28 QALYS per 1000 patients treated), even in the context of an imperfect treatment delivery environment.

Affiliation: Dept. of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America; Robert Wood Johnson Clinical Scholars Program, University of Michigan, Ann Arbor, Michigan, United States of America; Center for Clinical Management Research, VAAAHS, Ann Arbor, Michigan, United States of America.

ABSTRACT

Objectives: In this study, we developed a model of presymptomatic treatment of Alzheimer disease (AD) after a screening diagnostic evaluation and explored the circumstances required for an AD prevention treatment to produce aggregate net population benefit.

Methods: Monte Carlo simulation methods were used to estimate outcomes in a simulated population derived from data on AD incidence and mortality. A wide variety of treatment parameters were explored. Net population benefit was estimated in aggregated QALYs. Sensitivity analyses were performed by individually varying the primary parameters.

Findings: In the base-case scenario, treatment effects were uniformly positive, and net benefits increased with increasing age at screening. A highly efficacious treatment (i.e. relative risk 0.6) modeled in the base-case is estimated to save 20 QALYs per 1000 patients screened and 221 QALYs per 1000 patients treated.

Conclusions: Highly efficacious presymptomatic screen and treat strategies for AD are likely to produce substantial aggregate population benefits that are likely greater than the benefits of aspirin in primary prevention of moderate risk cardiovascular disease (28 QALYS per 1000 patients treated), even in the context of an imperfect treatment delivery environment.

pone-0114339-g004: One-way sensitivity analyses.The y-axis for each panel displays the change in the number of expected QALYs with the implementation of a treatment intervention vs. no intervention in a 55 year-old population as treatment efficacy, harm and probability of discontinuation are varied across the x-axis. A) RRR ceiling B) RRR slope C) Probability of Harm D) Magnitude of Harm E) Probability of Discontinuation.

Mentions:
These analyses demonstrate how net benefit changed as each primary parameter of interest was varied (Figure 4). As expected, both treatment efficacy parameters (treatment RRR ceiling and temporal slope) are quite influential, with a nearly linear increase in net benefit as efficacy increases and plateauing at very high levels of efficacy. Given the low treatment-related harm assumed in our base-case, even modestly effective therapies (e.g. RR 0.95) produce net benefits, however, there is a steep decline in net benefit as treatment-related harm increases. Still, as long as an AD preventive treatment is highly effective, a net benefit persists even at a relatively high probability of harm – as high as 10%/year. Medication discontinuation had a marked effect on net utility, subjects discontinuing treatment incurred the short-term risks of harm but treatment benefits require long-term treatment. Net benefit falls by almost half when the discontinuation rate reaches 3% per year and half again at 6% per year.

pone-0114339-g004: One-way sensitivity analyses.The y-axis for each panel displays the change in the number of expected QALYs with the implementation of a treatment intervention vs. no intervention in a 55 year-old population as treatment efficacy, harm and probability of discontinuation are varied across the x-axis. A) RRR ceiling B) RRR slope C) Probability of Harm D) Magnitude of Harm E) Probability of Discontinuation.

Mentions:
These analyses demonstrate how net benefit changed as each primary parameter of interest was varied (Figure 4). As expected, both treatment efficacy parameters (treatment RRR ceiling and temporal slope) are quite influential, with a nearly linear increase in net benefit as efficacy increases and plateauing at very high levels of efficacy. Given the low treatment-related harm assumed in our base-case, even modestly effective therapies (e.g. RR 0.95) produce net benefits, however, there is a steep decline in net benefit as treatment-related harm increases. Still, as long as an AD preventive treatment is highly effective, a net benefit persists even at a relatively high probability of harm – as high as 10%/year. Medication discontinuation had a marked effect on net utility, subjects discontinuing treatment incurred the short-term risks of harm but treatment benefits require long-term treatment. Net benefit falls by almost half when the discontinuation rate reaches 3% per year and half again at 6% per year.

Bottom Line:
Net population benefit was estimated in aggregated QALYs.In the base-case scenario, treatment effects were uniformly positive, and net benefits increased with increasing age at screening.Highly efficacious presymptomatic screen and treat strategies for AD are likely to produce substantial aggregate population benefits that are likely greater than the benefits of aspirin in primary prevention of moderate risk cardiovascular disease (28 QALYS per 1000 patients treated), even in the context of an imperfect treatment delivery environment.

Affiliation:
Dept. of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America; Robert Wood Johnson Clinical Scholars Program, University of Michigan, Ann Arbor, Michigan, United States of America; Center for Clinical Management Research, VAAAHS, Ann Arbor, Michigan, United States of America.

ABSTRACT

Objectives: In this study, we developed a model of presymptomatic treatment of Alzheimer disease (AD) after a screening diagnostic evaluation and explored the circumstances required for an AD prevention treatment to produce aggregate net population benefit.

Methods: Monte Carlo simulation methods were used to estimate outcomes in a simulated population derived from data on AD incidence and mortality. A wide variety of treatment parameters were explored. Net population benefit was estimated in aggregated QALYs. Sensitivity analyses were performed by individually varying the primary parameters.

Findings: In the base-case scenario, treatment effects were uniformly positive, and net benefits increased with increasing age at screening. A highly efficacious treatment (i.e. relative risk 0.6) modeled in the base-case is estimated to save 20 QALYs per 1000 patients screened and 221 QALYs per 1000 patients treated.

Conclusions: Highly efficacious presymptomatic screen and treat strategies for AD are likely to produce substantial aggregate population benefits that are likely greater than the benefits of aspirin in primary prevention of moderate risk cardiovascular disease (28 QALYS per 1000 patients treated), even in the context of an imperfect treatment delivery environment.